METHOD OF SYNTHESIZING CAMPTOTHECIN - RELATING COMPOUNDS

Abstract

The present invention is to prepare efficiently 2'-amino-5' -hydroxypropiophenone corresponding to the AB-ring part of camptothecin (CPT) skeleton and a tricyclic ketone corresponding to the CDE-ring part in order to provide efficiently CPT by the total synthesis, which is a starting material for irinqtecan hydrochloride and various kinds of camptothecin derivatives, and to provide stably CPT and its derivatives.

(b) 1-19, Higashishinbashi 1-chome, Minato-ku, Tokyo 105-8660. JAPAN.
(c) JAPAN
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.
1

The present invention relates to a process for synthesizing camptothecinrelated compound(s) . More particularly, the invention relates to a process for preparing intermediates related to the synthesis of camptothecin analogs having an anti-tumor activity and use of said intermediates, and relates to a total synthesis of camptothecin analogs.
Background Art
Camptothecin (hereinafter described as CPT) isolated from the bark, root, fruit, leaf and the like of Camtotheca acunimta o f Chinese origin is a pentacyclic alkaloid and is known to show the anti-tumor activity by inhibition of a nucleic acid synthesis. In the meantime, as to a camptothecin derivative the induction of diarrhea and the likeasasideeffectarereported (Gann to Kagaku Ryohou 17, pll5-120. 1990) , leaving a problem to cause disorder for the gastrointestinal tract, and therefore, various kinds of derivatives have been examined to reduce the toxicity, to increase the effect, and so on.
Thus, the inventors already reported 7-e thyl-1.0-[ 4-( 1-piper idino)-1-piper idino ] carbonyloxy camptothecin hydrochloride trihydrate (hereinafter described as CPT-11), the water soluble semisynthetic derivative of CPT, as a compound which is reduce in toxicity compared to CPT, and it is at present widely used as the anti-tumor agent (general name; irinotecan hydrochloride).
Camptothecin analogs such as CPT-11 can be derived by a chemical modification of CPT obtained from natural materials.
However, owing to an extremely low amount of CPT obtained from
2

natural materials such as Camtotheca acunimtati h ich is thestartingmaterial , it is anticipated that according to an increased demand of CPT-11 which is a useful derivative and the like, a sufficient supply of CPT becomes difficult notwithstanding a measure for the starting material supply such as afforestation. Although the total synthesis is also examined, it is the present situation that it has not yet been into practical use.
As a process by total synthesis is known the method of Shen. W. et al. represented by the below reaction scheme via Friedlander reaction of the aminopropiophenone and the tricyclic ketone (J. Org. Chem. 1993. 58, 611-617 "Concise Total Syntheses of dl-Camptothecin and Related Anticancer Drugs.", though there are problems that the steps are tedious, the yields are not sufficient and only the racememate is synthesized.

TWB
-7SDficnz 1h
D; Cur
this method is highly dangerous due to the necessity to use t-BuLi easily flammable in a large amount industrially, and the reaction at -78°Casa reaction temperature is required, making it impossible to enlarge the batch size. Further, owing to the necessity of a complicated temperature control in the total reaction system it was not an industrially practical reaction system.
Disclosure of Invention
4

It is an object of the invention to provide efficiently CPT, which is a start ing material for irinotecan hydrochloride and various kinds of camptothecin derivatives, and camptothecin analogs such as 7-ethy1-1O-hydroxycamptothecin . which is a key intermediate of the irinotecan hydrochloride synthesis, by a practical total synthesis. Particularly, it is an object of the invention to synthesize an intermediate corresponding to the AB-ring part of camptothecin skeleton and an intermediate corresponding to the CDE-ring part respectively, and further to synthesize camptothecin analogs using these intermediates.
Mode for Carrying Out the Invention
In view of these circumstances the inventors made an extensive research, and consequently as to the AB-ring part, made Compound (a) (5-hydroxy-2-nitrobenzaldehyde ) :

H
(a)

'NO,
astartingmaterial , andfoundameanstoprovide CPTand itsderivatives stably by an efficient preparation of 2'-amino-5'-hydroxypropiophenone corresponding to the AB-ring part of CPT skeleton, and as to the CDE-ring part starting from Compound (k) (2-methoxy-6-trimethyl silylpyridine (MTP ) ) :

TMS

(k)

wherein TMS represents a trimethy1sily 1 group, and Me represents
5

a methyl group. )
foundameans to provide CPTand its derivativesstablybyan efficient preparation of a tricyclic ketone corresponding to the CDE-ring part of CPT skeleton, and established a total synthetic process for CPT analogs by an appropriate combination of these means without using natural materials, finishing the invention.
Namely, the invention relates to a process for preparing 2'-amino-5'-hydroxypropiophenone corresponding to the AB-ring of CPT skeleton according to the route;

CHO NO2
CHO
"a,
(a)

(c)

(wherein R represents a protective group.),
and relates to a total synthetic process of CPT analogs by the appropriate combination of a process for the tricyclic ketone corresponding to the CDE-ring part of CPT skeleton comprising particularly synthesis of 3 -formy1- 4 -iodo-2-methoxy-6 -trimethylsilylpyridine (Compound (1)) from 2-methoxy-6-trimethylsilylpyridine (Compound (k)) or 3-hydroxymethy1-4 -iodo-2-methoxy-6-trimethylsilylpyridine (Compound (v)) by improving and optimizing a process according to the synthetic route;
6

Particularly, the invention relates to a process for preparing 2 ' -amino-5'-hydroxypropiophenone to synthesize camptothecin analogs, wherein from Compound (a):

(a)

Compound (b ) : R0W^YCH0

b)

is produced; and from Compound (b) Compound (c) OH
~
is produced; and from Compound (c) Compound (d)

'N02

(d)

is produced; and from Compound (d) Compound (e)

NHa

(e)

8
is produced; wherein R is a protective group which can be deprotected by a catalytic reduction.
Also, the invention relates to the above process, wherein the protective group which can be deprotected by a catalytic reduction is a benzyl group.
Further, the invention relates to the above process, wherein it contains one or more steps selected from the group consisting of
(1) a step to obtain Compound (b) mixing Compound (a) , a benzylation reagent and a base, and stirring said mixture in solvent under reflux;
(2) a step to obtain Compound (c) by dropping Grignard reagent to Compound (b) under an inert gas atmosphere;
(3) a step to obtain Compound (d) mixing Compound (c) and an oxidizing agent and stirring the mixture;
(4) asteptoobtain Compound (e) by a catalytic reduction of Compound (d) .
Further, the invention relates to the above process wherein in the step (1) the solvent is dimethylformamide .
The invention also relates to the above process wherein in the step (2) the Grignard reagent is vinyl magnesium bromide.
Further, the invention relates to the above process wherein in the step (3) the oxidizing agent is Jones reagent, manganese dioxide or TEMPO-(2, 2,6,6 -tetramethy1piperidine-1-oxy1)- sodium hypochlorite.
9

is produced.
Further, the invention relates to the above process, wherein it contains one or more steps selected from the group consisting of
(1) a step to obtain Compound (c') by dropping Grignard reagent to Compound (a) under an inert gas atmosphere;
(2) a step to obtain Compound (d') mixing the Compound (c') and an oxidizing agent and stirring the mixture; and
(3) astep toobtain Compound (e)'by a catalytic reduction of Compound
(d" ) .
The invention also relates to the above process wherein in the step (1) the Grignard reagent is vinyl magnesium bromide.
Further, the invention relates to the above process wherein in the step (2) the oxidizing agent is Jones reagent, manganese dioxide or TEMPO-sodium hypochlorite.
The invention also relates to use of 2'-amino-5'-hydroxypropiophenone, which is obtained by the above process, to the preparation of camptothecin analogs.
11

Further, the invention relates to a process for preparing camptothecin analogs, comprising reaction of 2'-amino-5'-hydroxypropiophenone obtained by the above process and a tricyclic ketone.
The invention also is a process for preparing the tricyclic ketone to synthesize camptothecin analogs, wherein from Compound (k) :

TMS

(k)

(wherein TMS is a trimethylsily1 group, and Me is a methyl group. ) or Compound (v):

(v)

(wherein TMS is a trimethylsilyl group, and Me is a methyl group.) Compound ( 1 ) :
OM»
(I)
(wherein TMS is a trimethylsilyl group, and Me is a methyl group.) is produced; and from Compound (1) Compound (m):
12

TMS ^^1

(m)

(wherein TMS is a trimethylsilyl group, and Me is a methyl group. ) is produced; and from Compound (m) Compound (n):

TMS
(n)

(wherein TMS is a trimethy1sily1 group. Me is a methyl group, and
Et is an ethyl group . )
is produced; and from Compound (n) Compound (o):

™S Et'^orf*

(o)

(wherein TMS is a trimethylsilyl group. Me is a methyl group, and
Et is an ethyl group. )
is produced; and from Compound (o) Compound (p) ;
>Me
(P)
™S ^0*Vt°
13

(wherein TMS is a trimethylsilyl group. Me is a methyl group, and
Et is an ethyl group. )
is produced; and from Compound (p) Compound (q):

HO Et

(q)

(wherein Me is a methyl group, and Et is a ethyl group.) is produced; and from Compound (q) Compound (r):

(r)

(wherein Me is a methyl group, Et is an ethyl group, and Pr is a
propyl group . )
is produced; and from Compound (r) Compound (s):

HO Et
(s)

(wherein Et is an ethyl group, and Pr is a propyl group.) is produced; and from Compound (s) Compound (t):

*BHO
(t)

14

(wherein Et is an ethyl group, and tBu is a t-butyl group.) is produced; and from Compound (t) Compound (h) :

(h)

(wherein Et is an ethyl group.)
is produced; and wherein it contains one or more steps selected
from the group consisting of;
(1) a step to obtain Compound (1) mixing Compound (k), a lithiating agent, a formylation reagent and an iodination reagent;
(2) astep toobtainCompound (m) mixing Compound (1), crotyl alcohol, triethylsilane and an acid, and reacting said mixture without use o f solvent; .
(3) a step to obtain Compound (1) mixing Compound (v), a byproduct in the step (2), with an oxidizing agent and a base;
(4) a step to obtain Compound (n) mixing Compound (m),a palladium catalyst, a base and a phase-transfer catalyst, and refluxing said mixture in solvent;
(5) a step to obtain Compound (o) mixing Compound (n), an osmium catalyst, a co-oxidizing agent, a base and an asymmetric reagent;
(6) a step to obtain Compound (p) mixing Compound (o), a base and iodine, and refluxing said mixture in an alcohol-water mix liquid;
(7) a step to obtain Compound (q) mixing Compound (p) and a
desilylation-iodination reagent;
(8) a step to obtain Compound (r) mixing Compound (q), a palladium
catalyst and a base, and reacting said mixture in 1-propanol under
15

a carbon monoxide gas atmosphere;
(9)asteptoobtain Compound(s)mixingCompound(r)andademethylation
reagent, and reacting said mixture at room temperature:
(10) a step to obtain Compound (t) reacting Compound (s) under the
presence of t-butyl acrylate and a base.
Further, the invention relates to the above process wherein in the step (1) the lithiating agent is n-butyl lithium.
The invention also relates to the above process wherein in the step (1) the reaction temperature is the constant temperature of -30 to -40°C.
Further, the invention relates to the above process wherein in the step (3) the oxidizing agent is TEMPO-sodium hypochlorite.
The invention also relates to the above process wherein in the step (4) the base is potassium carbonate or N.N-diisopropylethylamine .
Further, the invention relates to the above process wherein in the step (4) the solvent is tetrahydrofuran, or a diisopropyl ether-acetnitrile-water mix liquid.
The invention also relates to the above process wherein in the step (5) the osmium catalyst is potassium osmate(VI).
Further, the invention relates to the above process wherein in step (6) the iodine against Compound (o) is in 4 equivalent.
The invention also relates to the above process wherein in the step (7) the desilylation-iodination reagent is iodine-silver trifluoroacetate or N-chlorosuccinimide-sodium iodide.
Further, the invention relates to the above process, wherein Compound (q) is purified chemicallyby purification steps comprising a step to add the reaction product obtained by the step to produce
16

Compound (q) from Compound (p) to an aqueous alkaline solution and to stir; a step to add anorganic solvent and to stir, followed by removal of the organic layer; and a step to make the aqueous layer acidic and to extract with an organic solvent.
The invention also relates to the above process wherein the aqueous alkaline solution is an aqueous sodium hydoxide solution: Further, the invention relates to the above process wherein the organic solvent is chloroform.
The invent ion also relates to the above process , wherein Compound (q) is purified optically by purification steps comprising a step to dissolve the reaction product obtained by the step to produce Compound (q) from Compound (p) in a high polarity solvent, followed by lamination of a low polarity solvent; and a step to filter a precipitate which is followed by concentration of the filtrate to dryness under reduced pressure.
Further, the invention relates to the above process wherein' the high polarity solyent is chloroform.
The invention also relates to the above process wherein the low polarity solvent is n-hexane .
Further, the invention relates to the above process wherein in step (10) the base is potassium carbonate.
The invent ion also relates to use of thetricyclicketoneobtained
by the above process to the preparation of camptothecin analogs.
Further, the invention relates to the process for preparing
camptothecin analogs wherein the tricyclic ketone obtained by the
above process is reacted with 2'-amino-5'- hydroxypropiophenone.
The invention also relates to the above process, wherein the
2'-amino-5'-hydroxypropiophenone is
2'-amino-5 '-hydroxypropiophenone obtained by the above process.
17

Further, the invention relates to the above process, wherein the tricyclic ketone and 2 ' -amino-5 ' -hydroxypropiophenone are mixed and said mixture is reacted under an inert atmosphere.
The invention makes it becoming possible to prepare efficiently 2'-amino-5'-hydroxypropiophenone corresponding to the AB-ring part of the CPT skeleton by adopting these constituents and makes it possible to put a total synthesis of CPT into practical use. Additionally, as to the intermediate Compound (c') and Compound (d' ) in the process of the invention there is yet no report of their synthesis, and therefore they are useful novel compounds.
The invention also makes it possible to carry out practically an asymmetric synthesis of compound(s)byadoptingtheseconstituents, whereby 'compound(s) have the skeleton becoming the CDE-ring part (the tricyclic ketone part) in the CPT skeleton.
As to the synthesis of 2'-amino-5'-hydroxypropiophenone of the AB-ring in the CPT skeleton. a process for preparing 2'-amino-5'-hydroxypropiophenone comprises one or more steps of the followings;
(1)the step tosynthesize5-benzyloxy-2-nitrobenzaldehyde(Compound (b')) from 5-hydroxy-2-nitrobenzaldehyde (Compound (a));
(2) the step to synthesize 1-(5-benzyloxy-2-nitrophenol) -2-propen-l-ol (Compound (c')) from Compound (b'):
(3) the step to synthesize 1-(5-benzyloxy-2-nitrophenol) -2-propen-l-one (Compound (d')) from Compound (C); and
(4) the step to synthesize 2'-amino-5'-hydroxypropiophenone
(Compound (e)) from Compound (d').
18

As a typical synthetic route, the following synthetic route

( wherein R is a protective group which can be deprotected by a catalytic
reduction)
is shown .
In the invention, in case R is a protective, group which can be deprotected by a catalytic reduction, it is not particularly limited, but typical examples are benzyl ether type protective groups such as a benzyl, methoxybenzyl, 2,6-dimethylbenzylor4-nitrobenzyl groups, and benzyl carbonate type protective groups such as a benzyloxycarbonyl group, though a benzyl group is expediently used particularly in view of a" reagent cost.
Further, as to Compound (a) which is the starting material, that synthesized by a known method, that chemically converted from a similar compound, that isolated and purified from various kinds of natural materials, and natural materials containing Compound (a) can be used. A commercially available reagent may also be used.
In the following the above steps (1) to (4) are explained more specifically.
In the step (l) . Compound (a) isdissolvedorsuspended insolvent.
19

followed by addition of a benzylation reagent and a base and by heating under stirring to afford Compound (b).
As solvent N,N-dimethylformamide (DMF), dimethyl sulfoxide, chloroform, acetonitrile , ethanol, water and the like can be used, and DMF is preferable particularly in view of solubility and reactivity.
The used amount of DMF may be three or more times based on that of Compound (a), preferably in the range of 3 to 20 times.
As a benzylation reagent any one can expediently be used if it is conventionally used. Illustrative of specific examples are benzyl chloride, benzyl bromide, benzyl iodide, phenyldiazomethane, dibenzyl carbonate and the like, and in particular benzyl chloride can expediently be used.
The used amount of a benzylation reagent may appropriately be prepared according to the reagent, though in case of using, for example, benzyl chloride, it is used in 1 to 5 equivalent based on that of Compound (a), preferably 1 to 2 equivalent.
As a base any one can expediently be used if it is conventionally used. Illustrative of specific examples are potassium carbonate, sodium carbonate/, cesium carbonate, sodium hydroxide, potassium hydroxide and the like, and in particular potassium carbonate can expediently be used.
The used amount of a base may appropriately be prepared according to the reagent, though in case of using, for example, potassium carbonate, it is used in 1 to 10 equivalent based on that of Compound (a), preferably 1 to 4 equivalent.
As a heating temperature it is in the range of 60 to 100°C, preferably 60 to 80°C.
20

Additionally, the reaction time is in the range of 0.5 to 24 hours, preferably 1 to 20 hours.
In the step (2), Compound (c) is obtained dropping Grignard reagent to Compound (b) under an inert gas atmosphere.
As an inert gas any one may be used in case it is a noble gas such as argon, helium, neon, krypton, xenon, radon or the like, or a gas of low reactivity such as nitrogen, and argon and nitrogen are preferable particularly in view of the cost.
As Grignard reagent any one can expediently be used if it is conventionally used. Illustrative of specific examples are vinyl magnesium bromide, vinyl magjiesium chloride, vinyl magnesium iodide and the 1ike, and in particularvinylmagnesium bromide can expediently be used.
The used amount of Grignard reagent may be prepared according to the reagent, though in case of, for example, vinyl magnesium bromide, it is used in 1 to 2 equivalent based on that of .Compound (b), preferablyl to 1.5 equivalent.
In case Grignard reagent is dropped to Compound (b) solution or on the contrary Compound (b) solution is dropped to Grignard reagent, synthesis of Compound (c) is possible, though in order-to reduce the production of the reduced type byproduct (hereinafter described as Compound (f))
(whereinRisaprotectivegroupwhichcanbedeprotectedbya catalytic reduction.), it is preferable to drop Grignard reagent to Compound (b ) solution.
21

As a used amount of solvent in the reaction, for example, tetrahydrofuran (hereinafter referred to as THF) may be in an amount of 10 to 100 times, and to reduce particularly production of the alcohol an amount of 50 to 100 times is preferable.
Also, the reaction temperature is preferably not more than 10°C, and to reduce particularly production of the alcohol -7 8 to -.4 0 ° C is preferable.
Additionally, the reaction period is 0.1 to 3 hours, and in particular, preferably, it is 0.5 to 1 hours.
In the step (3), Compound (d) can be obtained mixing Compound (c) with an oxidizing agent and stirring the mixture.
As an oxidizing agent any one can expediently be used if it is conventionally used. Illustrative of such oxidizing agents are. for example, manganese dioxide, Dess-Martin Periodinane, Jones reagent (Na2Cr207/H2S04) . PCC, PDC, DMSO/oxalyl chloride/triet hylamine (Swern oxidation), TEMPO-sodium hypochlorite and' the like. and in particular, manganese dioxide, Dess-MartinPeriodinane,Jones reagent and TEMPO-sodiumhypochlorite can preferably be. used.
As to these oxidizing agents, one prepared just beiore use is preferably used, and in case of, for example, manganese dioxide, one prepared just be fore use from potassium permanganate and manganese sulfate can expediently be used.
Theusedamountofanoxidizingagentmayappropriatelybeprepared according to the reagent, though in case of, for example, manganese dioxide, it is used in 2 to 50 times based on that of Compound (c), preferably 4 to 10 times.
As solvent, for example, chloroform, methylene chloride, ethyl acetate, benzene, toluene and the like can expediently be used,
22

and in particular, chloroform and methylene chloride are preferable.
The used amount of solvent is 5 to 50 times, preferably 10 to 20 times .
Further, the reaction time is 1 to 48 hours and in particular, 1 to 18 hours are preferable.
In the step (4), Compound (e) can be obtained by a catalytic reduction of Compound (d).
As a catalyst for reduction palladium-carbon, palladium hydroxide-carbon, rhodium-alumina and the like can expediently be used, and in particular, palladium-carbon and palladium hydroxide-carbon are preferable.
The used amount of acatalyst forreductionisO.01toO.5equivalent based on that of Compound (d), preferably 0.05 to 0.2 equivalent .
As solvent anyone can expediently be used if it is conventionally used, though ethyl acetate is preferable in view of solubility.
The used amount of solvent is 5 to 50 times, preferably 10 to 20 times.
Additionally, thereactiontimeisO . 1to24hoursandinparticular, preferably, it is 1 to 3 hours.
Further, instead of synthesizing Compound (e) via the above steps (1) to (4), from Compound (a):

(a)

(c")

is produced; and from Compound (c' ) Compound (d' )
23

is produced; and from Compound (d') Compound (e):

NHg
kAUu

(e)

can be produced. In this synthetic route. Compound (c') can be obtained dropping Grignard reagent to Compound (a) under an inert atmosphere. Further, Compound (d' )can be obtained mixing Compound (c;' ) and an oxidizing agent and stirring the mixture, and Compound (e) can be obtained by a catalytic reduction of Compound (d'). Here, Grignard reagent and the oxidizing agent which can be used are the same as those in the above steps (2) and (3) . In thissynthetic route, sincenoprotectinggroupisused, thesynthesisofthe AB-r ing part can simply be carried out.
Further, camptothecin analogs can be prepared by reacting Compound (e) obtained in thestep (4) orthesyntheticroutedescribed previously and a tricyclic ketone, though as tricyclic ketone like this, for example. Compound (h):

HO" Et
(h)

can be used.
As to synthesis of the CDE-ring part (the tricyclic ketone part) of the CPT skeleton, preparation of the tricyclic ketone is carried out via the following synthetic route.
24

JO
«

TMS

0)

CHO I

OMe
TMS^^I TMS' M

(m)

TMS

(n)

Et

TMS
TMS

*BuO
HO' Et
HO' " Et°
(s) ' W ' (h)
(wherein TMS is a trimethylsily1 group. Me is a methyl group, Et is an ethyl group, Pr is a propyl group, and lBu is a t-butyl group. )
As to the starting Compound (k) in the above synthetic route, that synthesized by the above Curran route (Josien, H.; Ko, S. B.; Bom.D. :Curran.D.P.Chera.Eur.J. 1998, 467-83)describedpreviously. that chemically converted from a similar compound that isolated and purified from various kinds of natural materials, or a natural material itself, which contains Compound (k). can be used.
A preferable synthetic process for synthesizing the tricyclic ketone in the above synthetic route contains one or more steps from the 12 steps consisting of;
(1) in the step to synthesize 4-iodo-2-methoxy-6-trimethylsilyl -3-pyridinecarbaldehyde (hereinafter referred to as Compound (1)) from 2-methoxy-6- trimethylsilylpyridine (hereinafter referred to as Compound (k) ) , n-butyl lithium is used as a base and the reaction is carried out at the constant temperature of -30 to -40°C;
(2) in the step to synthesize 3-(2-butenyloxymethyl ) -4-iodo-2-
25

methoxy- 6-trimethy1silylpyridine (hereinafter referred to as Compound (m)) from Compound (1). a reaction solvent is not used;
(3) in the step to synthesize Compound (1) from 3-hydroxymethyl
-4-iodo-2-methoxy-6-trimethylsilylpyridine (hereinafter referred
to as Com pound (v) ) , TEMPO-sodium\ hypochloriteisusedas an oxidizing
agent;
(4) in the step to synthesize 4-ethyl-8-methoxy-6-
trimethylsilyl-lH-pyrano[3,4-c] pyridine (hereinafter referred to
as Compound (n)) from Compound (m). a mixed liquid of diisopropyl
ether, acetonitrile and water is used as a reaction solvent, and
N,N-diisopropylethylamine is used as a base;
(5) in the step to synthesize (S)-4-ethyl-3,4-dihydro-3,4-dihydroxy-8-methoxy-6-1 trimethylsilyl-lH-pyrano[3,4-c] .pyiridine (hereinafterreferred to as Compound(o)) fromCompound(n), potassium osmate(VI) is used as an osmium catalyst;
(6) in the step to synthesize (S)-4-ethyl-3,4-dihydro-4-hydroxy-8-methoxy-6-1 trimethylsilyl-3-oxo-lH-pyrano[3,4-c] pyridine (hereinafter referred to as Compound (p)) from Compound (o) , the reaction mixture is refluxed using iodine (4 equivalent) ;
(7) in the step to synthesize (S) -4-ethyl-3,4-dihydro-4-, hydroxy-6-iodo-8-methoxy-3-oxo-lH-pyrano[3,4-c] pyridine (hereinafter referred to as Compound (q)) from Compound (p). N-chlorosuccinimide-sodium iodide is used in acetic acid;

(8) in the step to purify Compound (q) chemically, the mixture is added with a basic solution such as aqueous sodium hydroxide solution to make a solution alkaline, washed with an organic .solvent such as chloroform, and then the water layer after acidification is extracted with an organic solvent such as chloroform;
(9) in the step to purify Compound (q) optically. Compound (q) is
■ 26

dissolved in a high polarity solvent such as chloroform and laminated with a low polarity solvent such as n-hexane to give precipitate which is removed by filtration, followed by concentration of the filtrate;
(10) in the step to synthesize propyl ( S ) -4-e thy 1 -3 , 4 -di-hydro-4-
hydroxy-8-methoxy-3-oxo-lH-pyrano[3.4-c]pyridine-6- carboxylate
(hereinafterreferredtoas Compound(r) ) from Compound (q) , palladium
acetate is used as a palladium catalyst;
(11) in the step to synthesize propyl (S)-4-ethyl-3,4,7,8-
tetrahydro-4-hydroxy-3,8-dioxo-lH-pyrano[3.4-c] pyridine-6-
carboxylate (hereinafter referred to as Compound (s) ) from Compound
(r). the reaction is carried out at room temperature;
(12) in the step to synthesize 1 , 1-dimethylethyl (S)-4-ethyl
-3.4,8.10-tetrahydro-4.6-dihydroxy-3,10-dioxo-lH-pyrano[3,4-f]
indolidin-7-carboxylate (hereinafter referred to as Compound (t))
from Compound (s), Michel addition is carried out using potassium
carbonate. ' /
Further, (13) in the step to obtain SN-38 from (S)-4-ethyl-7,8-dihydro-4-hydroxy-lH-pyrano[3,4-f]indolidin-3, 6 , 10(4H)-trione (hereinafter referred to as Compound, (h)) and Compound (e), SN-38 can be expediently be obtained carrying out the reaction in an inert gas atmosphere to afford SN-38 expediently.
In the following, the above 13 steps are explained more speci fically.
In the step of (1), Compound (k) isdissolved insolvent, followed by addition of a litiation, formylation and iodination reagents and stirring to afford Compound (1).
As solventtetrahydrofuran (THF) . diethyl ether, hexane, heptane and the like can be used, and THF is preferable particularly in
27

view of solubility and reactivity.
As a litiation reagent any one can expediently be used if it is conventionally used. Illustrative of specific examples are n-butyllithium, s-butyl1ithium , t-buty11ithium , lithium diisopropylamide (LDA), lithiumbis(trimethylsilyl)amide. ( Li HMDS ) and the like, and n-butylli thium can expedientlybe used particularly in view of handling and reactivity.
The used amount of a litiation reagent may appropriately be prepared according to the reagent, though in case of using, for example, n-butyllithium, it is -used in 2 to 10 equivalent based on that of Compound (k), preferably 2 to 5 equivalent.
Illustrative of specific examples of a formylation reagent are N-formyl-N,N',N'-trimethylethylenediamine, dimethylformamide (DMF) and the like, and N- f ormyl-N. N' ,N'- trimethylethylenediamine is expediently used considering the subsequent iodination.
The used amount of a formylation reagent, for example-, in case of using N-formyl-N,N',N'-trimethylethylenediamine is used in 1 to 10 equivalent based on that of Compound (k), preferably 1 to 3 equivalent.
As an iodination reagent iodine, N-iodosuccinimide (NIS) and the like can be used, and iodine is preferable particularly in view of the cost and reactivity.
The used amount of an iodination reagent is used in 1 to 10 equivalent basedon that of Compound (k), preferably 1 to 5 equivalent. The react ion temperature is in therangeof 0 to-78°C, preferably the constant temperature of- -30 to -40°C.
In the step of (2), Compound (1) is added with crotyl alcohol, triethylsilane and an acid and stirred without using solvent to afford Compound (m).
28

As the used amount of crotyl alcohol, it is used in 1 to 10 equivalent basedon that of Compound (k) , preferably 2 to 5 equivalent . As the used amount of triethyl si lane, it is used in 1 to 10 equivalent basedon that of Compound (k) , preferably 1 to 4 equivalent . As an acid trifluoroacetic acid (TFA). sulfuric acid, methanesulfonic acid, hydrochloric acid and the like can be used, and TFA is preferable particularly in view of reactivity.
The used amount of an acid, for example, in case of TFA is 1 to 15 equivalent based on that of Compound (1), preferably 5 to 10 equivalent .
In the step of (3), Compound (1) can be obtained by dissolving Compound (v), a byproduct in the step of (2), in solvent, followed by addition of an oxidizing agent and a base, and stirring.
As solvent any one can expediently be used i f it is conventionally used. II lustrativeofsudhsolvent aredichloromethane, chloroform, actonitrile, toluene, n-hexane and the like, and toluene and n-hexane are preferable particularly in view of reactivity.
Illustrative of oxidizing agents are manganese dioxide, Dess-Martin Periodinane, Jones reagent (Na2Cr207/H2S04) . PCC, PDC, DMSO-oxalyl chloride-triet hylamine (Swern oxidation), TEMPO-hypochlorite and the like, and in particular, TEMPO- hypochlorite is preferable, more preferably TEMPO-sodium hypochlorite .
As the used amount of an oxidizing agent, for example, in case of TEMPO-sodium hypochlorite. TEMPO isused in 0 . 001 to 0.1 equivalent based on that of Compound (v), preferably 0.005 to 0.02 equivalent. Additionally, sodium hypochlorite is used in 1 to 5 equivalent, preferably 1 to 2 equivalent.
As a base any one can expediently be used if it is conventionally used. Illustrative of such bases are sodium bicarbonate, sodium
29

carbonate,potassium carbonate, calcium carbonate,sodiumhydroxide, calcium hydroxide, triethyl amine and the like, with sodium bicarbonate being particularly preferable.
As the used amount of a base, for example, in case of sodium bicarbonate, it is used in 1 to 10 equivalent based on that of Compound (v), preferably 2 to 4 equivalent.
The reaction temperature is in the range of -10 to 30°C, preferably not -10 to 10°C particularly to suppress a side reaction.
Additionally, the reaction period is in the range of 0.5 to 10 hours, preferably 0.5 to 5 hours.
In the step of (4). Compound (m) is dissolved in solvent, added with a palladium catalyst, a base and a phase-transfer catalyst, and refluxed to afford Compound (n).
As solvent acetonitrile , tertrahydrofuran (THF). diisopropyl ether (IPE), diethyl ether, toluene, water and the like can be used, and acetonitrile, THF, IPE and water are preferable particularly in view of ' reactivity, more preferably THF or an acetonitrile-IPE-water mix liquid.
As a palladium catalyst palladium acetate, tetrakis-
(triphenylphosphine)palladium, dichlorobis-
(triphenylphosphine)pa1ladium, palladium chloride and the like can expedientlybeused, and palladiumacetate is preferable particularly in view of reactivity.
The used amount of a palladium catalyst is in 0 . 01 to 1 equivalent based on that of Compound (m), preferably 0.05 to 0.2 equivalent. As a base any one. can expediently be used if it is conventionally used. 11lustrativeof such bases are, for example, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, triethylamine (TEA), N,N-diisopropylethy1 amine (DIPEA). sodium
30

hydroxide, potassium hydroxide and the like, with potassium carbonate and DIPEA being particularly preferable.
The used amount of a base,-for example, in case of DIPEA is in 1 to 20 equivalent based on that of Compound (m), preferably 5 to 10 equivalent.
-As a phase-transfer catalyst any one can expediently be used if -it is a quaternary ammonium salt or crown ether which are conventionally used, with tetrabutylammonium bromide being particularly preferable.
The used amount of a phase-transfer catalyst, for example, in case of tetrabutylammonium bromide is in 0.1 to 3 equivalent based on that of Compound (m), preferably 0.5 to 1.5 equivalent.
Further, the reaction period in case of using THF is in the range of 1 to 20 hours, preferably 4 to 10 hours. In case of using an acetonitrile-IPE-water mix liquid it is in the range of 0.5 to 10 hours, preferably 1 to 5 hours.
In the step of (5), Compound (n) is dissolved in an alcohol-water mix liquid, .added with an osmium catalyst, a co-oxidizing agent, an asymmetric catalyst, a base and methanesulfonamide , and stirred to afford Compound (o).
Illustrative of alcohols are methanol, ethanol , 1-propanol, isopropanol (IPA), 1-butanol, 2-butanol, t-butyl alcohol and the like, and t-butyl alcohol is preferable particularly in view of reactivity.
As an osmium catalyst osmium tetraoxide, potassium osmate(VI) and the like can expediently be used, and potassium osmate(VI) is preferable particularly in view of handling.
The used amount of an osmium catalyst is in 0 . 001 to 0 . 1 equivalent based on that of Compound (n), preferably 0.002 to 0.01 equivalent.
31

As a co-oxidizing agent potassium hexacyanoferrate(III), N-methymorphol ine N-oxide (NMO) and the like can expediently be used,and potassiumhexacyanoferrate(III) is preferable particularly in view of the reactivity.
The used amount of a co-oxidizing agent, for example, in case of potassium hexacyanoferrate(III). is used in 1 to 10 equivalent based on that of Compound (n), preferably 2 to 5 equivalent.
Illustrative of asymmetric catalystsare (DHQD)2PYR. (DHQD)2PHAL _ (DHQD)2AQN and the like, and (DHQD)2PYR is preferable particularly in view of the optical yield.
The used amount of an asymmetric catalyst, for example, in case of (DHQD)2PYR. is used in, 0.005 to 0 . 1 equivalent based on that of Compound (n), preferably 0.01 to 0.05 equivalent.
As a base sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and the like can be used, and potassium carbonate is preferable particularly in view of the reactivity.
The used amount of a base, for example, in case of potassium carbonate, is in 1 to 20 equivalent based on that of Compound (n), preferably 4 to 10 equivalent.
The used amount of methanesulfonamide is in 0.1 to 5 equivalent based on that of Compound (n), preferably 0.5 to 2 equivalent.
Thereactiontemperatureisintherangeof-10 to 30°C, preferably -10 to 10°C.
In the step of (6) , Compound (o) is dissolved in solvent, added with a base and iodine, and refluxed to afford Compound (p).
Illustrative of solvent are methanol, ethanol, 1-propanol, isopropanol (IPA), water and the like, with a methanol-water mix liquid being particularly preferable in view of reactivity.
32

As a base any one can expediently be used if it is conventionally used. Illustrative of such bases are sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and the like, with calcium carbonate being particularly preferable.
Theusedamountof abase, forexample, incaseofcalciumcarbonate, is in 1 to l0 equivalent based on that of Compound (o) , preferably 2 to 5 equivalent.
The used amount of iodine is in 1 to 10 equivalent based on that of Compound (o), preferably 3 to 5 equivalent. Additionally, the reaction period is in the range of 0.5 to 20 hours, preferably 1 to 5 hours.
In the step of (7), Compound (p) is dissolved in solvent, and reacted under iodine-silver trifluoroacetate (hereinafter referred to as I2-CF3CQOAg ) or N-chlorosuccinimide-sodium iodide (hereinafter referred to as NCS-Nal) to afford Compound (q).
As to solvent, in case of I2-CF3COOAg dichloromethane, carbon tetrachloride, chloroform and the like are expedient, and in particular, dichloromethane is preferable. Additionally, in case of NCS-Nal acetic acid, acetonitrile and the like can be used, and acetic acid is preferable particularly in view of reactivity.
As to the used amount of I2-CF3COOAg , I2 is used in l to l0 equivalent based on that of Compound (p), preferably 2 to 4 equivalent. Additionally, CF3COOAg is used in 1 to 10 equivalent, preferably 2 to 4 equivalent .
As to the used amount of NCS-Nal , NCS is used in 1 to 20 equivalent based on that of Compound (p), preferably 5 to 8 equivalent. Additionally, Nal is used in 1 to 20 equivalent based on that of Compound (p), preferably 5 to 8 equivalent.
' 33

The reaction" temperature in case of using I2-CF3COOAg is 10 to 60 °C. preferably 20 to 40°C. Further, in case of using NCS-Nal it ' is 20°C to a reflux temperature, preferably 50 to 80°C.
Additionally, the reaction period is in the range of 5 to 4 8 hours, preferably 15 to 24 hours.
In the step of (8), Compound (q) is added with a basic solvent, for example, such as aqueous 0.2N sodium hydroxide, and stirred to give the lactone-ring opening compound (Compound (u)): OMe OH
(u)
w C "ONa+ HO" 'Et
(wherein Me is a methyl group, and Et is an ethyl group.), which
is soluble in the aqueous basic solution. When washing the solution
with an organic solvent, a neutral-basic substance moves to an organic
layer. The organic layer is separated, followed by acidification
of the water layer with an acid and extraction with an organic solvent
to recover Compound (q) in good purity.
The basic solvent is in the range of 0.01 to 5N, preferably 0.1 to IN, more preferably 0.2 to 0.5N.
Illustrative of used bases are potassium hydroxide, calcium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate . and the like, with sodium hydroxide being particularly preferable.
As an organic solvent any* one can expediently be used if it -is conventionally used. Illustrative of such solvent are dichloromethane, chloroform, ethyl acetate , toluene, diethyl ether, diisopropyl ether and the like, and in particular, with dichloromethane and chloroform being particularly preferable.
Illustrative of used acids are hydrochloric acid , su1furicacid,
34

nitric acid, acetic acid, phosphoric acid, trifluoroacetic acid and the like, with hydrochloric acid being particularly preferable. In the step of (9) , Compound (q) is dissolved in a high polarity solvent, and laminated with a low polarity solvent to precipitate crystals which are filtered. The filtrate is concentrated under-reduced pressure to dryness. The obtained crystals are 'racemic, and a more optically purified Compound (q) is obtained as a residue. As a high polarity solvent chloroform, dichloromethane, ethyl acetate, methanol, ethanol, propanol and the like can be used, and in particular, chloroform is preferable.
The used amount of a high polarity solvent, for example, in case of chloroform, is l to 10 ml. Preferably 3 to 6 ml , against Compound (q) lg.
Illustrative of low polarity solvent are n-hexane. n-heptane, diethyl ether and the like, with n-hexane being particularly preferable.
The ratio of a high polarity solvent: a low polarity solvent is, for example, in case of chloroform:n-hexane. is in the range of 10:1 to 1:20, preferably 2:1 to 1:2.
The temperature in the crystallization procedure is not more than room temperature, preferably not more than 5°C.
In the step of (10). Compound (q) is dissolved in 1-propanol , added with a palladium catalyst and a base, and reacted under a carbon monoxide gas atmosphere to afford Compound (r).
As to a palladium catalyst. palladium acetate,
tetrakis-(triphenylphosphine)palladium, dichlorobis-
(triphenylphosphine)palladium, palladium chloride and the like can expedientlybe used, and pa 11 adiumacetate is preferable particularly in view of the reactivity.
35

Theusedamountofapalladiumcatalyst is in 0.005 to 0.5 equivalent based on that of Compound (q), preferably 0.01 to 0.1 equivalent. As a base any one can expediently be used if it is conventionally used. II lustrative o f such bases are, forexample. sodium carbonate, potassium carbonate. calcium carbonate, cesium carbonate, tr iethylamifie (TEA), N, N-di i sopropyle thylamirie (DIPEA), solium hydroxide , potassium hydroxide and the like, withpotassiumcarbonate being particularly preferable.
The used amount of a base, for example, in case of potassium ^carbonate, is in 1 to 20 equivalent based on that of Compound (q), preferably 4 to 10 equivalent.
The reaction temperature is in the range of 20°C to a reflux
temperature, preferably not more than 5Q°C to a reflux temperature.
In the step of (11), Compound (r) is dissolved in solvent, added
with a demethylation reagent, .and reacted at room temperature to
afford Compound (s).
As solvent acetonitrile, chloroform, dichloromethane ; toluene andthelikecanbeused,andinparticular,acetonitrileispreferable. Illustrative of demethylation reagents are chlorotrimethylsilane-sodium iodide, iodotrimethylsilane, hydriodic acid, hydrobromic acid and the like, with chlorotrimethylsilane-sodium iodide being particularly preferable. The used amount of a demethylation reagent, for example, in case of chlorotrimethylsilane-sodium iodide, is in 1 to 10 equivalent based on that of Compound (r), preferably 2 to 5 equivalent.
In the step of (12). Compound (s) is dissolved in solvent, added with a base, and stirred under an inert gas atmosphere. The obtained mixture is dropped with t-butyl acrylate, and stirred under an inert gas atmosphere to afford Compound (t).
36

As to solvent, dimethylsulfoxide (DMSO) , N.N-dimethylformamide (DMF) and the like can expediently be used, and DMSO is preferable particularly in view of reactivity.
As a base potassium carbonate, sodium carbonate, sodiumhydroxide, potassium hydroxide and the like can be used, and in particular, potassium carbonate is preferable.
The used amount, of a base,- for example, in case of potassium carbonate, is in 1 to 20 equivalent based on that of Compound (s), preferably 2 to 5 equivalent.
As an inert gas any one may be used in case it is a noble gas such as argon, helium, neon, krypton, xenon, radon or the like, or a gas of low receptivity such as nitrogen, and argon and nitrogen are preferable particularly in view of the cost.
The used amount of t-butyl acrylate is in 1 to 20 equivalent based on that of Compound (s), preferably 8 to 12 equivalent.
The reaction temperature is in the range of 20 to 8 0 ° C, preferably 40 to 60°C. '
Further, the reaction period is in the range of 5 to 48, hours, and in particular, it is preferably not more than 24 hours in order to avoid particularly decomposition of Compound (t) produced.
In the step of (13) , Compound (h) and Compound (e) are dissolved insolvent, addedwithanacid, andheatedunderaninertgasatmosphere and stirring to afford SN-38.
As solvent toluene, acetic acid and the like can expediently be used, and in particular, a toluene-acetic acid mix liquid is preferable.
As an inert gas any one may be used in case it is a noble gas such as argon, helium, neon, krypton, xenon, radon or the like, or a gas of low reactivity such as nitrogen, and argon and nitrogen
37

are preferable particularly in view of the cost.
As an acid toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and the like can be used, and toluenesulfonic acid is preferable particularly in view of reactivity.
The used amount of an acid , forexample, in case o f toluenesulfonic acid, is 1 to l00mg based on that of Compound (h) lg, preferably 10 to 30mg.
The used amount of Compound (e) is in 1 to 3 equivalent based on that of Compound (h), preferably 1 to 1.5 equivalent.
The reaction temperature is in the range of 50°C to a reflux temperature, preferably 80°C to a reflux temperature.
In the following, the invention will be illustrated in more detail by way of examples, but the invention is not limited to these.
[Example 1] Synthesis of Compound (b') HO.^. .a a
YY . J= ► YY
^^N02 in DMF ^^N02
(a) ' (b
Wherein Bn is a benzyl group.
Compound (a) (38.5 g, 0.230 mol) was dissolved in 116 mL of
DMF or acetone. Potassium carbonate (33.4 g, 0.242 mol, 2.1 eq.)
and 27.8 mL (0.242 mol, 1.05 eq.) or 59.95 mL (0.461 mol, 2 eq. )
of benzyl chloride were added to the stirred solution of Compound
(a) at room temperature under argon atmosphere. After the addition,
the mixture was heated at 60 °C and vigorously stirred for 20 hours
with periodical checks the content of Compound (a) . After Compound
(a) was not detected anymore, the mixture was filtered by suction.
38

The solid material was washed with the same solvent used for the reaction. The filtrate and the washing were combined; and the solvent was evaporated under reduced pressure. And water (300 mL) was added to the residue. The mixture was stirred and the precipitates were filtered by suction and dried in air. After air-drying, the filtered material was dissolved in 170mL of ethyl acetate. This solution was added to 1 L of hexane with stirring. The precipitated solid material was filtered by suction, washed with 300 mL of a mixture of ethyl acetate and hexane (1:10) and dried under reduced pressure.
Experiment (Exp.) 1 and 2, in which were discriminated by the amount of the benzyl chloride was varied and in Exp. 3, acetone was used as the reaction solvent.
[Table 1]

Reaction solvent Amount of benzyl chloride Reaction time Isolated yield
Exp. 1 DMF 1.05eq.. 20 hours 94%
Exp. 2 DMF 2.00eq. 1 hour 94% ,
Exp. 3 acetone 2.00eq. 18 hours i
-:' less than limit of detection
As shown in Table 1, 20 hours were required for th completion of the reaction with the yield of 94% when 1. 05 eq. of benzyl chloride was used (Exp. 1). When 2.00 eq. of the benzyl chloride was used (Exp. 2), the reaction was finished in 1 hour and the yield was 94%. Three -fold amounts of DMF was minimal requirement for the
39

reaction, otherwise the stirring was disturbed by precipitating the solid material during the reaction. When acetone was used as the reaction solvent, the reaction did not proceed even under reflux condition for 18 hours.
HPLC operation conditions
Column: Inertsil ODS-2, 5 Dm, 4.6 mm IDx250 mm (GL
science-made)
Temperature: constant temperature about 40 °C
Mobile phase: water : acetonitrile mixture(1 : 1)
Flow rate: lmL/min
Detect: 220 nm
[Example 2] Synthesis of Compound (c') (1)
OH
a
(b-) (C) (f)
Wherein Bn is a benzyl group.
Compound (b') (1.0 g, 3.8 9 mmol) was dissolved in 20 mL of THF. Vinylmagnesium bromide (1.0 M THF solution, 5.84 mL, 5.84 mmol, 1.5 eq.) was added dropwise to the ice-cooled, stirred solution of Compound (b') under argon atmosphere over 15 minutes. During the addition, the internal temperature was kept within 3 to 10 °C. After the stirring for 1 hour, the reaction solution was added to asaturatedaqueoussolutionof ammoniumchloride (20mL) withstirring, and then to the solution 20 mL of ethyl acetate and 4 mL of hexane were added, and the obtained organic layer was washed with 20 mL of water and an aqueous saturated solution of sodium chloride
40

successively, and dried over 3g of sodium sulfate. The solvent was evaporated under reduced pressure to give Reaction product A.
A THF solution (20 mL) of Compound (b' ) prepared as mentioned above was added dropwise to an ice-cooled solution of vinylmagnesium bromide (1.0 M THF solution, 5.84 mL) under argon atmosphere over 15 minutes. During the addition; the internal temperature was kept within 3 to 10 °C. After the stirring for 1 hour, the reaction solution was added to a saturated aqueous solution of ammonium chloride (20 mL) with stirring and then to the solution 20 mL of ethyl acetate and 4mL of hexane were added, and the organic layer was separated and washed with 20 mL of water and a saturated aqueous solution of sodium chloride and dried over 3 g of sodium sulfate. The solvent was evaporated under reduced pressure to give Reaction product B.
Reaction product A and B were purified through silica gel column chromatography (ethyl acetate : hexane = 1 : 20) to give Exp. 4 from Reaction product A and Exp. 5 from Reaction product B, respectively.
41

[Table 2]

Yield of Compound (c' ) Yield of Compound (f) (peak area %)
Exp. 4 84.0% 3.5%
Exp. 5 26.8% 11.3%
As shown in Table 2, when the Grignard reagent was added to the solution of Compound (b'), the yield of the product increased by 57% and formation of Compound (f), a byproduct, was suppressed.
HPLC operation conditions; refer to the Example 1.
[Example 3] Synthesis of Compound (cy) (2)
Compound (b') (1.0 g, 3.89 mmol) was dissolved in 10 to 100 mL of THF. Vinylmagnesium bromide (l.0 M in THF, 5.84 mL, 5.84 mmol, 1.5 eq.) was added dropwise to the stirred solution of Compound
(b') under argon' atmosphere over 15 minutes. After the stirring for 1 hour, the reaction solution was added to a saturated aqueous solution of ammonium chloride (20 mL) with stirring and then to the solution 20 mL of ethyl acetate and 4 mL of hexane were added, and the organic layer was separated and washed with 20 mL of water and a saturated aqueous solution of sodium chloride successively, and dried over 3g of sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by the same manner described in Example 2 (Exp. 4 and 5) . Exp. 6 represents the results of the reaction at 20 °C using 20-fold amount of the solvent. Exp. 7 to 9 represent the results of the reaction at 3 °C using 10-fold, 40-fold, 100-fold amount of the solvent, respectively. The results
42

[Example 4] Synthesis of Compound (d') (1)
OH O
k^v-^s^s^ oxidizing reagent B^s^v^Av^'
XXT ' XXT
(C) (tf)
Wherein Bn is a benzyl group.
(1) Preparation of manganese dioxide:
An aqueous solution of manganese sulfate penta-hydrate (122 g/150 mL, 0.506mol) and 117 mL of 40% sodium hydroxide were added to an aqueous solution of potassium permanganate (96.0 g/600 mL, 0.607mol) at room temperature with starring. After stirring for 18 hours, the solid material was filtered by suction and washed with water. The -obtained solid material was dried in air to give 91.2 g of manganese dioxide.
(2) Synthesis of Compound (d')
Compound (c') (2.00 g, 7.02mmol) was dissolved in 20 mL of chloroform, dichloromethane or ethyl acetate. Manganese dioxide 8.00g (4-fold amount, 92.0mol, 13eq.) preparedby the above mentioned method was added to the vigorous stirred solution of Compound (c') at 25 °C under argon atmosphere. The mixture was vigorously stirred for 15 hours. After the starting material was not detected anymore, the mixture was filtered by suction. The obtained solid material was washed with 20 mL of chloroform. The filtrate and the washing were combined, and the solvent was evaporated under reduced pressure. Exp. 10 to 12 were obtained.
44

[Table 4]

Reaction solvent Reaction time Remained starting material (peak area%) Yield
Exp. 10 chloroform 15 hours *~ 91%
Exp. 11 dichloromethane 3 hours "*" 79%
Exp. 12 ethyl acetate 24 hours 8% _
-: less than limit of detection
As shown in Table 4, when chloroform or dichloromethane was used as the reaction solvent, Compound (c') was synthesized in good yields . In particular, the reaction time was shortened to one third when dichloromethane was used as the reaction solvent. On the other hand, Compound (c') was remained even after 24 hours when ethyl acetate was used.
[Example 5] Synthesis of Compound (d') (2)
An aqueous solution of sodiumhypochlorite (available chlorine min. 5.0%; 42 mL) and sodium hydrogen carbonate aqueous solution
(7 .1 gin 60 mL of water) were added to a vigorously stirred, ice-cooled mixture of 7.0 g (3.5mmol) of Compound (c'), toluene (70 mL), ethyl acetate (70 mL), water (10 mL) and 38.3 mg (1 mol%) of TEMPO under ice cooling (at 2 to 6 °C, 55 min). After 5 minutes, 0.4% (HPLC, peak area%) of the starting material was detected. The mixture was placed still and the separated organic layer taken and was washed with a mixture of potassium iodide and potassium hydrogen sulfate
45

Wherein Bn is a benzyl group.
To an ice-cooled stirred solution of 1.84g (6.50 mmol) of Compound (d') in 37mL of ethyl acetate, 0.69 g (0.65 mmol, 10 mol%) of 10% palladium carbon was added under argon atmosphere . The mixture was vigorously stirred at 25 °C under hydrogen atmosphere and a part of the mixture was taken as a sample for HPLC, periodically. The reaction mixture was filtered and the filtrate was evaporated. Exp. 13 to 14 were obtained.
46

Compound (k) (5.0 g, 0.028 mol) was dissolved in anhydrous THF (about 66 mL). The reaction was carried out as described in Example 12 at constant temperature at around -35 °C. The n-hexane layer obtained from the reaction mixture was washed with diluted hydrochloric acid (the same amount of the organic layer).
After the washing, the organic layer was dried over sodium sulfate, filtered and a part of the filtrate was analyzed by HPLC under the condition' given in Example 12. The results were shown in Table 7.
[Table 7] The analytical results of each the hexane layer after washed with diluted hydrochloric acid

As shown in Table 7, Compound (k) was almost removed by washing with the diluted hydrochloric acid. When 1.0 mol/mL and more concentrated hydrochloric acid was used for the washing. Compound (1) was obtained in good purity. 2-methoxy-6- trimethylsilylpyridine 3-carbaldehyde (MTPC), the formylated intermediate of Compound (k) , was hardly removed by this method.
[Example 14] Purification of Compound (1) (stepwise washings
with diluted hydrochloric acid) ' . "
Compound (k) (5.0 g, 0.028 mol) was dissolved in anhydrous THF (about 66 mL) . The reaction was carried out as described in Example 12 at constant temperature at around -35 °C. The n-hexane layer obtained from the reaction mixture was washed in turn (top to bottom) with the diluted hydrochloric acid listed in Table 8
(the same amount of the organic layer).
After the -washing, the aqueous acidic layer was separated, neutralized with sodium carbonate and then extracted with n-hexane. The organic layer was dried over magnesium sulfate, filtered and a part of the filtrate was analyzed by HPLC under the conditions given in Example 12. The results are summarized in Table 8.
[Table 8] The analytical results on the hexane extracts from the neutralized aqueous layer, which was obtained by washing the original hexane layer with diluted hydrochloric acid in order as follows (top to bottom).
59

[Example 16] Purification of Compound (1) (recovery as hydrochloric acid salt)
Compound (k) (5.0 g, 0.028 mol) was dissolved in anhydrous THF (about 66 mL) . The reaction was carried out as described in Example 12 at constant temperaturearound-35°C. Thereactionmixture
(10 g) was dissolved in 10 N hydrochloric acid (10 mL) and Stirred
~\ ■ ■ ■
at room temperature. The yellow precipitates were filtered and washed with a small amount of 10 N hydrochloric acid and the material was dissolved in water (about 10 mL) . The pH of the aqueous solution was adjusted to about 8 by adding sodium hydrogen carbonate, and the mixture was extracted with hexane and the organic layer was evaporated under reduced pressure to dryness.
The residue was analyzed by HPLC under the conditions given in Example 15. The results are shown in Table 10.
[Table 10] The analytical results on the extracts by neutralizing the hydrochloric acid salt obtained in 10 mol/L hydrochloric acid.

and the material was washed with n-hexane (6 mL x 3) . The filtrate and the washing were combined and washed with water (9 mL x 2), dried over anhydrous sodium sulfate and then evaporated under reduced pressure to dryness. The residue was purified through silica gel column chromatography with n-hexane-ethyl acetate (95:5) as the eluent.
Exp. 21 in Table 12 was the results of an experiment conducted under the reported conditions; Josien, H.; Ko, S. B.; Bom, D.; Curran, D. P., Chem. Eur.J. 1998, 4, 67-83. Curran, D. P.; Ko, S. B.; Josien, H., Angew. Chem. Int. Ed. Engl. 1995, 34, 2683-2684.
The ratio of the endo and exo forms of each the purified product was measured by HPLC. As shown in Table 12, satisfactory selectivity (endo - exo ratio) and isolated yield were obtained when THF was used as the reaction solvent under refluxed conditions (Exp. 25 - 27). The isolated yields of (Exp. 25 - 27) were highr than that of the reported conditions (Exp. 21) by 10% or more.
[Table 12]

QCH3 KJOSO^HJO
JT KjF^CNJe
^A^JL^ (DHQD)2PYR
(CH3)3Si y MeSOjNH2 (CH3)3Sf
C2H5 in aq. t-BnOH
n o
To a solution of potassium fericyanide (195.7 g, 0.*59 mol),
potassium carbonate, (82.lg, 0.59mol) andmethanesulfonamide (37.7
g, 0.40 mol) in water (990 mL) , (DHQD) PYR (4 .36 g, 4.95 mmol) and
potassium osmate (VI) dihydrate (1.0 mmol) were added and the mixture
was stirred at aroud 5 °C for 1 hr. To the stirred mixture, Compound
(n) (77.8 g, 0.18 mol, content: 61.5%) was added and the resulting
mixture was stirred at the temperature for additional 20hrs . Powdered
sodium sulfite (74.9 g) was added to the mixture and the stirring
was continued at the temperature for 30 min. The insoluble material
in the mixture was filtered on a Celite pad and the material on
the pad was washed with ethyl acetate (4 times, total 770 mL) . The
organic layer of the filtrate was separated and the aqueous layer
was further extracted with ethyl acetate (770 mL) . The combined
organic layers were dried over anhydrous sodium sulfate, filtered,
and evaporated under reduced pressure to dryness. The residue was
purified through silica gel column chromatography with a mixture
of dichloromethane - ethyl acetate (4:1) as the eluent; silica gel
(280 g, Fuji Silysia PSQ100B). Compound (o); umber solid.
As shown in Table 13, using potassium osmate as the oxidant
effected the equal level of the isolated yield and enantio excess
in place of highly volatile osmium (VIII) oxide.
69

To a solution of Compound (o) (70 g) in a mixture of methanol and water (10:1, 1.0 L), iodine (the amount is given in Table 14)
and powdered calcium carbonate (47.1 g) were added at ambient
i
temperature with stirring. The reaction mixture was stirred at given temperature and period in Table 14.
One litter of 10% sodium sulfite and chloroform (1.0 L) were added to the mixture and the resulting mixture was stirred at ambient temperaturefor30min.Theinsolublematerialwasremovedbyfiltration and the organic layer of the filtrate was separated. The aqueous layer was extracted with chloroform (500 mL x 2) . The extracts were
70

combined, dried over anhydrous sodium sulfate, filtered and then evaporated under reduced pressure to dryness.
Using 4 equivalent of iodine under reflux conditions, this reaction was completed in 5 hrs, about one tenth of that of the reported conditions with comparable yields.
[Table 14]

AsolutionofCompound (s) (0.50g)indimethylsulfoxide(DMSO, 7 mL) in the presence of an inorganic base (potassium or cesium carbonate, 0.4 g) was stirred at 50 °C under argon atmosphere for 20min. To the stirred mixture tert-butyl acrylate (1.8 g) was added dropwise and the resulting mixture was stirred at 50 °C under argon atmosphere for 24 hrs. Water (10 mL) and concentrated hydrochloric acid (1 mL) were added to the ice-cooled mixture and the mixture was extracted with a mixture of toluene and ethyl acetate (4:1, 7 mL x 4). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to dryness (Exp. 42 - 43). The residue was assayed by HPLC (as follows).
As shown in Table 16, Compound (t) was obtained in 72% yield using cesium carbonate as the base (Exp. 42), on the other hand, inexpensive potassium carbonate was used as the base, the yield was equal level with the Exp. 42.
[Table 16]
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CPT-11
SN-38B-11 (1.00 g, 1.7mmol), obtained as described in Example 32, was dissolved in 0.1 N hydrochloric acid (20 mL) by heating at around 80 °C. Acetonitrile (100 mL) was added to the solution and the mixture was gently stirred at ambient temperature for 15 hrs . The precipitates were filteredby suction and dried under reduced pressure and then humidified. CPT-11: pale yellowcrystalline powder, 0.95 mg (89.9% yield). Industrial Applicability
By use of the synthetic process of the invention highly pure 2' -amino-5'-hydroxypropiophenone and tricyclic ketone- can be synthesized in a short time with a high recovery yield, and by use of these as intermediates a total synthesis of CPT analogs can efficiently be carried out.
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is produced; and from Compound (b) Compound (c) OH
(c)
~x£r
'NO2
is produced; and from Compound (c) Compound (d):

"xxir
'NO2

(d)

is produced; and from Compound (d) Compound (e):

'NHz

(e)

is produced; wherein R is a protective group which can be deprotected by a catalytic reduction.
2 . A process according to claim 1, wherein the protective group which can be deprotected by a catalytic reduction is a benzyl group.
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3. A process according to claim 1 or 2, wherein it contains one or more steps selected from the group consisting of
(1) a step to obtain Compound (b)by mixing Compound (a), a benzylation reagent and a base, and stirring said mixture in solvent under reflux;
(2) a step to obtain Compound (c) by dropping Grignard reagent to Compound (b) under an inert gas atmosphere;
(3) a step to obtain Compound (d)by mixing Compound (c) and an oxidizing agent and stirring the mixture; and
(4) a step to obtain Compound (e) by a catalytic reduction of Compound (d) .
4 . A process according to claim 3, wherein in the step (1) the solvent is dimethylformamide.
5. A process according to claim 3, wherein in the step (2 ) the Grignard reagent is vinyl magnesium bromide.
6. Aprocess according to claim 3, wherein in the step (3) the oxidizing agent is Jones reagents, manganese dioxide or TEMPO-sodium hypochlorite.
7. Compound represented by formula (c'):
JnaY^Y^^
(c') N02
(wherein Bn is a benzyl group.
OH Br
8. Compound represented by formula (d'
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(wherein Bn is a benzyl group.).

9. A process for preparing 2'-amino-5'- hydroxypropiophenone to synthesize camptothecin analogs, wherein from Compound (a):
HON
XX
is produced; and from Compound (c") Compound (d") is produced; and from Compound (d") Compound (e):

(e) NH2
is produced.
10. A process according to claim 9, wherein it contains one or more,
steps selected from the group consisting of
(1) a step to obtain Compound (c") by dropping Grignard reagent to Compound (a) under an inert gas atmosphere;
(2) a step to obtain Compound (d") by mixing Compound (c") and-an oxidizing agent and stirring the mixture; and
(3) a step to obtain Compound (e) by a catalytic reduction of Compound (d").
11. Aprocess according to claim 10, wherein in the step (1) the Grignard
reagent is vinyl magnesium bromide.
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12 . Aprocess according to claimll, wherein in the step (2) the oxidizing agent is Jones reagent, manganese dioxide or TEMPO-sodium hypochlorite.
13. Use of 2'-amino-5'-hydroxypropiophenone, which is obtained by the process according to any one of claims 1-6 and 9-12, in the preparation of camptothecin analogs.
14. Aprocess for preparing camptothecin analogs, comprising reaction of 2'-amino-5'-hydroxypropiophenone, obtained by the process according to any one of claims 1-6 and 9-12, and a tricyclic ketone.
15. A process according to claim 14, wherein the tricyclic ketone and 2' -amino-5' -hydroxypropiophenonearemixed, andsaidmixture is reacted under an inert gas atmosphere.
16 . Aprocess according to claim 14 or 15, wherein the tricyclic ketone is a compound represented by formula (h):
(wherein Et is an ethyl group).
17. A method of synthesizing camptothecin-relating compounds as claimed substantially as herein described with forgoing description.
Dated this 14th Day of June 2007

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ABSTRACT
The present invention is to prepare efficiently 2'-amino-5' -hydroxypropiophenone corresponding to the AB-ring part of camptothecin (CPT) skeleton and a tricyclic ketone corresponding to the CDE-ring part in order to provide efficiently CPT by the total synthesis, which is a starting material for irinqtecan hydrochloride and various kinds of camptothecin derivatives, and to provide stably CPT and its derivatives.
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